Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: a randomized phase II trial

A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required. Electronic supplementary material The online version of this article (10.1007/s00262-020-02498-8) contains supplementary material, which is available to authorized users.


Background
The prognosis of patients with castration-resistant prostate cancer remains poor.
Treatments that can provide stable disease control with long-term survival benefits are needed. One such treatment is considered to be the combination therapy of a cancer vaccine with chemotherapy. However, the optimal combination therapy using a cancer vaccine with docetaxel for chemotherapy-naïve patients with castration-resistant prostate cancer remains unknown.

Aims
We aim to examine whether a novel cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce cytotoxic T lymphocytes in combination with docetaxel and dexamethasone enhances the anti-tumor effects in patients with castration-resistant prostate cancer.

Study design and population
This is a double-blind, placebo-controlled, randomized phase 2 study.
Chemotherapy-naïve patients with progressive castration-resistant prostate cancer will be enrolled from 10 medical centers in Japan.

Inclusion criteria
The subjects must satisfy the following conditions.
1. Patients must be diagnosed as prostate cancer pathologically at the initial treatment.

Patients who had progressive disease after androgen deprivation therapy (ADT) either
by surgical castration, gonadotropin-releasing hormone or antagonist treatment.
Progressive disease while receiving ADT, defined by any 1 of the following: 1) At least two consecutive rises in serum PSA obtained at a minimum of 1-week intervals.
2) Measurable disease with 50% increase in the sum of the cross products of all measurable lesions, or the development of new measurable lesions by RESIST.
3) Non-measurable (bone) disease consisting of new areas of uptake by bone scan consistent with metastatic disease compared to previous imaging.
3. Patients have serum PSA level 2 ng/mL 4. Anti-androgen therapy is discontinued for at least 4 weeks before the first vaccination for patients receiving flutamide and 6 weeks for those receiving bicalutamide.
7. Written informed consent must be obtained from patients.
8. Patients must be more 20 year-old.
9. Patients must be at a score level of 0-1 of performance status (ECOG).
10. Patients must be expected to survive more than 6 months.

Exclusion criteria
The following patients must be excluded: 1. Patients who had received chemotherapy using docetaxel any time before the treatment.
2. Patients who had received pre-therapies including chemotherapy or immunotherapy within 28 days before the treatment.
3. Patients who had received radiotherapy or strontium-89 within the last 8 weeks before the treatment.
4. Patients with severe symptoms (active and severe infectious disease, circulatory disease, respiratory disease, kidney disease, immunodeficiency, disturbance of coagulation). 10. Patients who are difficult to participate in this trial because of psychiatric symptoms. 11. Patients who are judged inappropriate for the clinical trial by doctors.

Randomization
After assessment of eligibility and appropriate consent, eligible patients are randomly assigned in a 1:1 ratio to receive either KRM-20 with docetaxel and dexamethasone (study arm) or placebo with docetaxel and dexamethasone (control arm) using a minimization technique with the following stratification factors: age (<65 or 65 years old) and PSA (<20 or 20 ng/ml ) at the clinical research unit of Kurume University in Kurume, Japan.
Treatment with docetaxel and the study drug is repeated every 3 weeks for up to 5 cycles, and oral dexamethasone is continued once daily until the end of the study.
Dosing delay and reduction for docetaxel is permitted if toxic effects are noted.
Docetaxel may be held for less than 2 weeks until recovery and reduced to 60 or 50 mg/m 2 in the event of neutropenia (< 2,000/mm 3 ), platelets < 100,000/mm 3 , hemoglobin < 8 g/dl, total bilirubin  1·5 x ULM, transaminase  2 x ULM, or serum creatinine  2 x ULM. If docetaxel is held for more than 3 weeks, patients are removed from protocol treatment. After the study, patients who received protocol treatment will be followed up for 3 years for survival analyses.

Endpoints
The primary endpoint in this study was the comparison of each treatment arm for the rate of > 50% PSA decline from baseline. Based on the previous report, the assumed rate of > 50% PSA decline was 65% in the KRM-20 arm and 25% in the placebo arm.
The target sample size was 50 assuming an ineligibility rate of approximately 10%.
Sample size computation based on the large sample test was performed with the following assumptions: type I error rate = 0.05, power 80% and the ratio of the two groups as 1:1. Secondary endpoints are safety, immune responses, progression-free survival (PFS), and overall survival (OS). The Student's t-test and chi-square test will be used to compare quantitative and categorical variables among safety profiles and immune responses to the treatment, respectively. PFS and OS data for each arm will be analyzed using the Kaplan-Meier method. The log-rank test will be used to compare the survival curves, and Cox proportional hazard analysis to estimate hazard ratios (HR).
The confidence intervals (CI) reported are 95%. Statistical analyses are performed using SAS software version 9·1 (SAS Institute, Cary, NC) with a two-sided significance level of 5%. All analyses will be on an intention-to-treat basis.

Funder
The Ministry of Health, Labour and Welfare of Japan (ID 2014110358 to M. Noguchi).

Date trial started
Jul 1, 2013

Expected date of completion
Jul, 2017